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Duchenne Muscular Dystrophy (DMD)

Causes/Inheritance

Cause of DMD

Until the 1980s, little was known about the cause of any of the forms of muscular dystrophy. In 1986, MDA-supported researchers identified a gene on the X chromosome that, when flawed (mutated), causes both Duchenne and Becker muscular dystrophies.

Genes contain codes, or recipes, for proteins, which are important biological components in all forms of life. In 1987, the protein associated with this gene was identified and named dystrophin.

DMD occurs because the mutated gene fails to produce virtually any functional dystrophin. (Individuals with Becker MD genetic mutations make dystrophin that is partially functional, which protects their muscles from degenerating as badly or as quickly as in DMD.)

Lack of dystrophin causes muscle damage and progressive weakness, beginning in early childhood.

The dystrophin protein transfers the force of muscle contraction from the inside of the muscle cell outward to the cell membrane. Because it connects the center of the muscle cell to the periphery, the dystrophin protein is extremely long. One end is specialized for linking to the muscle interior and the other end is specialized for linking to a variety of proteins at the cell membrane. The long middle section, called the rod domain, is taken up by a series of repeating units called spectrin repeats.

The repeated spectrin units in the middle of the protein play an important role in linking the two ends but studies have shown that the exact number of these units is not critical for the function of the protein as a whole. Many cases of DMD are caused by mutations in the part of the gene that encodes this middle section. Production of the entire protein stops when the mutation is encountered.

The absence of dystrophin sets in motion a cascade of deleterious effects. Fibrous tissue begins to form in the muscle and the body’s immune system increases inflammation. In addition to its force-transfer role, dystrophin provides the scaffold for holding numerous molecules in place near the cell membrane. Loss of dystrophin displaces these molecules, with consequent disruptions in their functions.

Inheritance in DMD

DMD is inherited in an X-linked pattern, because the gene that can carry a DMD-causing mutation is on the X chromosome. Every boy inherits an X chromosome from his mother and a Y chromosome from his father, which is what makes him male. Girls get two X chromosomes, one from each parent.

Each son born to a woman with a dystrophin mutation on one of her two X chromosomes has a 50 percent chance of inheriting the flawed gene and having DMD. Each of her daughters has a 50 percent chance of inheriting the mutation and being a carrier. Carriers may not have any disease symptoms but can have a child with the mutation or the disease. DMD carriers are at risk for cardiomyopathy.

Although DMD often runs in a family, it's possible for a family with no history of DMD to suddenly have a son with the disease. There are two possible explanations:

The genetic mutation leading to DMD may have existed in the females of a family for some generations without anyone knowing it. Perhaps no male children were born with the disease, or, even if a boy in an earlier generation was affected, relatives may not have known what disease he had.

The second possibility is that the child with DMD has a new genetic mutation that arose in one of his mother’s egg cells. Since this mutation isn’t in the mother’s blood cells, it’s impossible to detect by standard carrier testing.

If a mother gives birth to a child with DMD, there’s always the possibility that more than one of her egg cells has a dystrophin gene mutation, putting her at higher than average risk for passing the mutation to another child. And once the new mutation has been passed to a son or daughter, he or she can pass it to the next generation.

A man with DMD can’t pass the flawed gene to his sons because he gives a son a Y chromosome, not an X. But he’ll certainly pass it to his daughters, because each daughter inherits her father’s only X chromosome. They’ll then be carriers, and each of their sons will have a 50 percent chance of developing the disease and so on.

Females and DMD

Why don’t girls usually get DMD? When a girl inherits a flawed dystrophin gene from one parent, she usually also gets a healthy dystrophin gene from her other parent, giving her enough of the protein to protect her from the disease. Males who inherit the mutation get the disease because they have no second dystrophin gene to make up for the faulty one.

Early in the embryonic development of a female, either the X chromosome from the mother (maternal X) or the one from the father (paternal X) is inactivated in each cell. The choice of which chromosome to inactivate is random. In each cell, there’s a 50 percent chance that either the maternal or paternal X chromosome will be inactivated, with the other left active.

Most of the time, it doesn’t matter how many inactivated maternal and paternal X chromosomes a female has. But when there’s a mutation in an X-chromosome gene, such as in the gene for dystrophin, it matters a lot.

If a girl or woman has to rely on too many X chromosomes with the dystrophin gene mutation (meaning the Xs with the functional dystrophin genes are mostly inactivated), she’s likely to develop symptoms of DMD or Becker MD.

Usually, however, girls don’t experience the full effects of DMD the way boys do, although they still have symptoms of muscle weakness. A minority of females with the mutation, called manifesting carriers, have some signs and symptoms of DMD.

For these women, the dystrophin deficiency may result in weaker muscles in the back, legs and arms that fatigue easily. Manifesting carriers may have heart problems, which can show up as shortness of breath or inability to do moderate exercise. The heart problems, if untreated, can be quite serious, even life-threatening.

In very rare instances, a girl may lack a second X chromosome entirely, or her second X may have sustained serious damage. In these cases, she makes little or no dystrophin (depending on the type of dystrophin mutation), and she develops DMD or BMD just as a boy would.